Depression is a pervasive psychiatric disease with significant associated personal, economic and medical costs. Early onset depression in childhood or adolescence is associated with particularly high costs, as an earlier age of onset is associated with a worse clinical course. Relapse rates are extremely high in depressed adolescents (40-65 % within 1 year). Understanding the biological risks factors for depression and the underlying pathophysiology of the illness are essential to reducing the costs associated with the illness and the development of new strategies in treating early onset depression. Previous research has shown that slow wave activity (SWA) regulation is impaired in adults with major depressive disorders (MDD) but is strongly sex-dependent. Men with MDD show a blunted response to sleep challenge compared to healthy controls, whereas women with MDD show a hyper-response to challenge compared to healthy women. To date, there are no published studies of sleep regulation in early onset MDD. The proposed study will determine if impaired SWA homeostasis also characterizes adolescents with MDD. Of primary interest are age-related changes in SWA homeostasis to test the hypothesis that depression associated with premature aging and whether the time course differs in boys and girls with MDD. The proposed work will also begin to assess the relationship between homeostatic response to challenge and symptoms of depression and whether sleep challenge improves mood differentially in boys and girls. The long-range objectives of this work are to determine the independent and interactive influence of sex and disease on sleep regulation, to improve understanding of the biological bases for sex differences in the symptoms and relative risks for depression and to develop intervention strategies informed by this work to reduce the differential biological risk factors for depression in boys and girls. The specific aims of this proposal are: 1. to evaluate slow-wave activity (SWA) in baseline sleep in 72 mature (Tanner Stage 5) depressed adolescent males and females (n=36/group) and 72 age- and gender-matched healthy non-depressed controls (HCs) 2. To evaluate sex differences in the regulation of SWA in response to a 3 hour sleep delay in depressed adolescents compared to HCs. 3. To compare age-related changes in SWA response to sleep-delay across group and sex. 4. To determine the relationship between clinical features of depression and SWA regulation to assess whether the most impaired SWA is associated with a worse clinical course and higher suicidal ideation and if mood improves with homeostatic challenge. PUBLIC HEALTH RELEVANCE: The proposed research is of very high public health relevance. Sleep disturbances are core features of depression and are among the most common residual symptoms of depression. By identifying whether sleep homeostasis is abnormal in early onset depression, we can begin to develop novel interventions that specifically target sleep and are likely to reduce residual symptoms and may reduce risk of relapse and recurrence.